xe2x80x9cThe invention relates generally to methods and apparatus for inducing hypothermia in an animal, and more particularly relates to methods and apparatus for warming a nasal passage, or a sinus, or the hypothalamus, or a combination of these, of an animal.xe2x80x9d
xe2x80x9cMore than half-a-million Americans suffer strokes every year, and a similar number suffer head trauma each year. Some of these people die of their injuries; however, most survive with some degree of neurological damage. Although many treatments and therapies have been attempted, none are very effective in reducing neurological damage following stroke, head trauma, or other such condition. One of the most effective therapies known for these and similar conditions is hypothermia, the lowering of body temperature. Even small reductions in body temperature after the initial injury has occurred can reduce damage and improve neurological outcome, if treatment is not delayed too long after the incident. In fact, hypothermia has been a confounding variable in animal experiments directed at discovering pharmacological compounds which may reduce neurological damage following experimentally-induced trauma; some compounds thought to be directly neuroprotective have instead been found to lower body temperature in the small-bodied experimental animals used in studies. When the body temperature of these animals is artificially maintained at the normal level during drug treatment, some of these promising drugs have been found not to be neuroprotective, revealing that the effective treatment was hypothermia, and not the drug. Accordingly, it is desireable to discover a method for inducing hypothermia in humans.
Body temperature is very well regulated in warm-blooded animals. However, the pharmacological compounds that may lower the body temperature of a mongolian gerbil or a rat (with large body surface areas compared to their small volumes) do not effectively produce hypothermia in larger animals such as humans. It is very difficult to cool humans due to our larger mass, smaller surface area in proportion to our volume, and our complex homeostatic mechanisms geared towards maintaining our body temperature.
However, although difficult, it is possible to cool large animals and humans. Hypothermia (the condition of lower-than-normal body temperature in a warm-blooded animal) has been investigated in animals for many years, and has been used on human patients (for example, in heart surgery) for more than forty years. It is known to reduce neurological damage otherwise resulting from cardiac arrest, stroke and trauma. Known methods for inducing hypothermia all involve cooling the outside or inside of an animal, sometimes in conjuction with drugs that disable the animal""s homeostatic responses. Present methods for inducing hypothermia include externally applied cold packs, ice blankets, infusion of cold saline into arteries and into the peritoneum of an animal, blowing air across an animal""s skin, wetting the skin or hair of an animal, and cooling the air around an animal. One method, preferred by some researchers, includes infusion of saline into the peritoneum of an animal in order to cool a large volume of blood and tissue in contact with the peritoneum. However, this is no simple procedure, but is an invasive procedure that requires puncture of the abdominal wall, infusion of cool or cold saline, and monitoring of fluid and electrolyte balance of the animal for the duration (and beyond) of the procedure. Hypothermia may also be a side-effect of general anesthesia during surgery.
However, these methods are impractical because they require trained personnel and dedicated equipment, and often induce discomfort in the animal or are invasive. In many of the above examples, careful co-ordination and oversight by medical personnel is required since drastic measures need be taken to overcome the normal operation of the animal""s physiological responses to cold. These responses include vasoconstriction, shunting of blood away from the limbs and retention of blood in the body core (away from cold blankets, wet skin, etc.) and shivering. Suppression of these responses by muscle relaxants, vasodilators and other drugs may also cause, as side-effects, suppression of other vital body functions associated with breathing, maintenance of blood pressure, heart rate, and other vital bodily functions. These side-effects, such as circulatory shock, may be serious. They increase risk and limit the effectiveness of hypothermia treatments in humans. Thus, there is at present no simple, effective method for inducing and maintaining hypothermia in an animal.
All of the above-mentioned methods for inducing hypothermia, with the possible exception of some potent centrally-active drug regimens that disable thermoregulation, must work to oppose the animal""s bodily efforts to maintain body temperature. Difficulties with these techniques arise because the homeostatic mechanisms and physiological responses involved in regulation of body temperature are among the most basic responses in warm-blooded animals. Cooling by cold blankets and dressings is uncomfortable, induces shivering which must be opposed by medication, and causes vasoconstriction which reduces blood flow to the cooled extremities, reducing the effectiveness of the cooling treatment. Cooling by intra-arterial infusion of cold blood or saline is invasive, of limited utility because of limited ability to deliver large volumes of cooled fluid, requires medical equipment and supervision, and may potentially cause vascular, cardiac and neurological (if emboli are created) side-effects. Pharmaceutical treatments that disable thermoregulatory responses often have other effects as well, and require active cooling measures such as those already mentioned in order to lower body temperature of a large animal. Thus, an ideal method for inducing hypothermia in a warm-blooded animal would not require drastic invasive measures or drugs, and would not oppose the animal""s physiological temperature control mechanisms, but would make use of them to achieve hypothermia.xe2x80x9d
Hypothermiaxe2x80x94Reduced Temperature
Hypothermia in an animal occurs when the body temperature, or temperature of a body region or organ, becomes reduced below the normal range. Hypothermia has been suggested or shown to be an effective treatment, or useful adjunct to other treatments, for a variety of diseases, including stroke, trauma to the central nervous system, and cancer.
Hypothermia (the condition of lower-than-normal body temperature in a warm-blooded animal) has been investigated in animals for many years, and has been used on human patients (for example, in heart surgery) for more than forty years. For example, U.S. Pat. No. 4,750,493 to Brader is directed to a method for cooling the extracranial area including the face during emergency care of cardiac arrest of severe shock in order to induce vasoconstriction and intracranial hypothermia. This invention is implemented by a topical cold pack described in the patent. U.S. Pat. No. 4,920,963 to Brader is also directed to a method and apparatus for cooling the extracranial area including the face during emergency care of cardiac arrest of severe shock, and discloses an apparatus which includes a watertight shroud for the head. U.S. Pat. No. 5,383,854 to Safar, Strezoski and Klain is directed to a cardio-pulmonary bypass apparatus adaptable to include a module that includes a heat exchanger capable of cooling the blood. U.S. Pat. No. 5,464,834 to Peglion, Goument, Millan and Rivet is directed to chemical compounds acting at a 5-HT1A receptor capable of inducing hypothermia in rats. U.S. Pat. No. 5,474,533 to Ward, Brown and Dzwonczyk is directed to a method and apparatus for treating patients suffering from cardiac arrest, shock, respiratory failure, hypothermia, hyperthermia, and head injury, capable of modulating a patient""s body temperature. U.S. Pat. No. 5,486,204 to Clifton is directed to a method for treating severe brain trauma with hypothermia. Hypothermia in human patients was induced by wrapping patients in cooling blankets, and administering drugs such as muscle relaxants and sedatives. All patents, both supra and infra, are hereby incorporated by reference in their entirety.
Hypothermia is Useful in the Treatment of Cancer
Hypothermia can be useful in the treatment of cancer. For example, lowered body temperature has been reported to reduce tumor metastasis in rats (Fisher et al. Archives of Surgery 98:347-351 (1969)) and in rabbits (Mandrik, Bulletin of Experimental Biology and Medicine (USSR) 47:66-70 (1959)). As long ago as 1940, Smith and Fay (American Journal of Clinical Pathology 10:1-12) reported that generalized hypothermia (as low as 74xc2x0 F., with patients maintained in the low 80s F. for up to 5 to 8 days) in cancer patients led to a reduction in pain and xe2x80x9cregressive changes in embryonic cells, particularly in carcinomaxe2x80x9d (Id. at page 10).
Hypothermia has been combined with other cancer treatments. Harrison (Journal of Laryngology and Otology 81:173-185 (1967)) treated 11 patients with head and neck cancer with chemotherapy during whole-body hypothermia by immersion in an ice bath, and suggested this be the treatment of choice for such patients. Scaly et al. (British Journal of Radiology 59(707):1093-1098 (1986)) reported that 10 of 21 mouth cancer patients were free of disease one year after treatment with hyperbaric oxygen and radiation with hypothermia.
Another, related strategy has been to lower the temperature of an animal with a tumor or tumors while locally maintaining the temperature of the cancerous tissue near normal body temperature. Regression and disappearance of tumors in hamsters made hypothermic has been reported where the tumors were artificially maintained at normal body temperature (Popovic and Masironi, American Journal of Physiology 211:463-466 (1966); Popovic and Masironi, Cancer Research 26:863-864 (1966)). Inducing hypothermia in animals with cancer while maintaining tumor tissue normothermic has enhanced the efficacy of chemotherapeutic agents. Popovic and Masironi (Cancer Research 26(1):2353-2356 (1966)) report the regression and disappearance of tumors in hamsters treated with at a 50 mg/kg dose of 5-fluoruracil (5-FU) during hypothermia, with the tumors maintained at normal body temperature, while the same dose of 5-FU did not affect tumor size when given to tumor-bearing animals that were not made hypothermic, or hypothermic animals whose tumors were also hypothermic. Thus, the combination of hypothermia, normothermic tumors, and chemotherapy (the tumors being maintained locally at normal body temperature during application of chemotherapy) has been found to be successful in treating cancer in laboratory animals.
Methods for maintaining cancerous tissue near to or above normal body temperature in a hypothermic animal are the same as those used to locally warm tissues, and have been known for many years. For example, radio-frequency electromagnetic heating for localized tissue heating in cancer therapy was described in 1962 by Shingleton et al. (Annals of Surgery 156:408-416). More modern methods include application of ultrasound heating, as for example, may be used to heat the prostate (see, e.g., U.S. Pat. No. 5,895,356 to Andrus et al., Apparatus and method for transurethral focused ultrasound therapy). Other methods include application of warm fluids, application of warm probes, application of radiation, such as infrared, microwave, or ultrasound radiation, inductive heating, and other means.
However, the methods and pharmacological compounds that may lower the body temperature of a laboratory rat or other small animal (with large body surface areas compared to their small volumes) do not effectively produce hypothermia in larger animals such as humans. Cooling humans and other large animals present difficulties due to our larger mass, smaller surface area in proportion to our volume, and our complex homeostatic mechanisms geared towards maintaining our body temperature.
Prior methods for inducing hypothermia include externally applied cold packs, ice blankets, infusion of cold saline into arteries and into the peritoneum of an animal, blowing air across an animal""s skin, wetting the skin or hair of an animal, and cooling the air around an animal. Hypothermia may also be a side-effect of general anesthesia during surgery.
Another method of inducing hypothermia comprises cooling by intra-arterial infusion of cold blood or saline. An example of such a method may be found in, e.g., U.S. Pat. No. 5,383,854 to Safar et al. A variant of the method of cooling the blood comprises insertion of a heat-exchange catheter into a body lumen of an animal effective to cool surrounding body fluids and tissues. Heat exchange catheters for inducing hypothermia are disclosed in Ginsburg, U.S. Pat. No. 5,837,003; Ginsburg, U.S. Pat. No. 5,486,208; Ginsburg, U.S. Pat. No. 6,033,383; Philips et al., U.S. Pat. No. 6,019,783; and Dobak, U.S. Pat. No. 6,0510,19.
However, these methods often induce discomfort in the animal or are invasive. In addition, drastic measures often need be taken to overcome the animal""s normal physiological responses to cold. These responses include vasoconstriction, shunting of blood away from the limbs and retention of blood in the body core (away from cold blankets, wet skin, etc.) and shivering. Suppression of these responses by muscle relaxants, vasodilators and other drugs may also cause, as side-effects, suppression of other vital body functions associated with breathing, maintenance of blood pressure, heart rate, and other vital bodily functions. These side-effects, such as circulatory shock, may be serious. They increase risk and limit the effectiveness of hypothermia treatments in humans. Thus, these prior methods when used alone do not provide a simple, effective method for inducing and maintaining hypothermia in an animal.
An ideal method for inducing hypothermia in a warm-blooded animal would not oppose the animal""s physiological temperature control mechanisms, but would make use of them to achieve hypothermia. Accordingly, improved methods of inducing hypothermia in larger animals, including human patients, are desired.
Hyperthermiaxe2x80x94Elevated Temperature
Hyperthermia in an animal occurs when the body temperature, or temperature of a body region or organ, becomes elevated above the normal range. Mild hyperthermia is a normal response to many forms of infection, as exemplified by fever. Hyperthermia has been suggested or shown to be an effective treatment, or useful adjunct to other treatments, for a variety of diseases.
Hyperthermia has been used to treat cancer. Observations of tumor regression in patients who had suffered from fevers were noted over a hundred years ago (Coley W B: Ann Surg 14:199 (1891)), and deliberate hyperthermia was reported as a treatment for tumors of the extremities nearly forty years ago (see, e.g., Stehlin, J S et al. Amer J Surg 105:60 (1963)). Whole body hyperthermia has been applied as a cancer treatment for a quarter of a century (see, e.g., Parks et al. in: F K Storm, ed. Hyperthermia in Cancer Therapy, G K Hall, Boston, Mass. 1995, pp. 407-446; Frazier H O, Proceed Am Acad Cardiovasc Perf 3:99 (1982); Herman et al., Cancer Treat Rep 66:259 (1982); Maeta et al. Cancer 59:1101 (1987)). Such work continues to the present day. For example, tumor cell apoptosis was reported in tumor-bearing mice exposed to hyperthermia for 6 to 8 hours (Burd et al., J. Cell. Physiol. 177:137 (1998)). Whole body hyperthermia has been found to relieve pain and to control tumor growth in a significant number of patients. A review on hyperthermia may be found in the International Consensus Meeting on Hyperthermia: Final Report, Valdagni et al., Int. J. Hyper. 7(5):837(1990).
Cancer cells are more sensitive to elevated temperature than normal cells (see, e.g., Chen et al. Int. J. Cancer 4:166 (1969), Giovanella et al. Cancer Res. 36:3944 (1976) and Robins et al., Radiol. Clin. North Am. 27:603 (1989)). Hyperthermia has been shown to enhance the cytotoxicity of drugs (Hahn et al., Cancer Res. 37:761 (1977); Marmor, Cancer Res. 39:2269 (1979)) and clinical studies have shown that the amount of hyperthermia is significantly related to clinical response in cancer patients receiving regional hyperthermia with their chemotherapy (see, e.g., Issels, et al., J. Clin. Oncol. 8:1818 (1990)). Similarly, hyperthermia has also been shown to enhance the cytotoxic effects of radiation treatments (see, e.g., Shidnia et al., Oncology 50:353 (1993), and of combined radiation and chemotherapy treatments.
In addition, novel cancer therapies may be enhanced by hyperthermia. For example, gene therapy utilizing heterologous gene expression linked to a heat shock protein promoter was enhanced by systemic hyperthermia in tissue culture, and hyperthermia enhanced the effects of adenovirus vectors containing heat-inducible interleukin expression on tumors in mice (Huang et al., Cancer res. 60:3435 (2000)).
Other diseases may be caused by infectious agents such as viruses, bacteria, fungi, parasitic or other organisms. A common reaction to many infections is fever, which may be directly helpful in overcoming the infection or may act to enhance the immune response and so aid in ridding the body of the infectious agents. Hyperthermia thus may be used to treat, or to enhance treatments, of infectious diseases. For example, hyperthermia has been used to treat HIV infections in humans (Ash et al., ASAIO J. 43:M830 (1997); Zablow et al., Int. J. Hyperthermia 13:577 (1997)).
Methods for raising body temperature, and so warming the whole body, include immersion in hot baths or situation of the subject in a hot chamber, use of microwave radiation, and chemical means, such as by administration of pyrogens. Some methods for local warming of tissue have been known for many years. For example, radio-frequency electromagnetic heating for localized tissue heating in cancer therapy was described in 1962 by Shingleton et al. (Annals of Surgery 156:408-416). More modern methods include application of ultrasound heating, as for example, may be used to heat the prostate (see, e.g., U.S. Pat. No. 5,895,356 to Andrus et al., Apparatus and method for transurethral focused ultrasound therapy). Other methods include application of warm fluids, application of warm probes, application of radiation, such as infrared, microwave, or ultrasound radiation, inductive heating, and other means. Examples of apparati that may be used to locally warm tissue or body fluids, or to locally cool tissue or body fluids, are disclosed in, for example, U.S. Pat. Nos. 5,486,208, 5,837,003, and 6,033,383 to Ginsburg; U.S. Pat. No. 6,019,783 to Phillips et al.; U.S. Pat. No. 6,051,019 to Dobak; U.S. Pat. No. 5,190,539 to Fletcher et al. and U.S. Pat. No. 5,417,686 to Peterson et al.). Regional heating may be more readily achieved or may be enhanced when combined with whole body hyperthermia (Croghan et al., Am. J. Clin. Oncol. 16:354 (1993)).
All of the above-mentioned methods for inducing hyperthermia, with the possible exception of some potent centrally-active drug regimens such as use of pyrogens, must work to oppose the animal""s bodily efforts to maintain body temperature. However, the homeostatic mechanisms and physiological responses involved in regulation of body temperature are among the most basic responses in warm-blooded animals. For this reason, these techniques suffer from the disadvantage that the animal""s normal physiological responses are actively opposing the efforts to induce hyperthermia. Thus, an ideal method for inducing hyperthermia in a warm-blooded animal would not oppose the animal""s physiological temperature control mechanisms, but would make use of them to achieve hyperthermia. Accordingly, improved methods of inducing hyperthermia in larger animals, including human patients, are desired.
xe2x80x9cKnown methods for inducing hypothermia all involve cooling the outside or inside of an animal, sometimes in conjunction with drugs that disable the animal""s homeostatic responses. It is new and unsuggested in the art to apply heat in an effort to reduce body temperature. The present invention is directed to a method and apparatus for applying heat to the hypothalamus of a warm-blooded animal in order to utilize the physiological mechanisms that regulate body temperature to effect a compensatory cooling response, thereby lowering body temperature. The present invention takes advantage of physiological temperature-regulatory mechanisms and makes direct use of their action, instead of striving to oppose or disable them.
It is well-known that the main brain center for regulation of body temperature is in the hypothalamus, a brain structure situated in humans just above the pituitaty gland. Decreasing the temperature of the hypothalamus, as occurs when core body temperature is reduced, triggers compensatoxy responses to cold, such as vasoconstriction and shivering. Conversely, warming the hypothalamus triggers compensatory responses that cool the animal, such as vasodilation and sweating. Thermoregulatory responses can be quite effective, as humans routinely live and work in environments where the external temperature is higher or much lower than normal body temperature.
The hypothalamus is very sensitive to small changes in body temperature. A temperature change of 0.2 degrees Celsius (.degree. C.) is sufficient to trigger sweating in a human subject. Sweating is a major mechanism for cooling in humans. Sweating will continue as long as the hypothalamic temperature is above its setpoint for temperature control. Thus, for example, if the temperature of the hypothalamus in a human patient is raised to about 0.2.. degree. C. or more above its setpoint, the patient will respond with such physiological cooling responses as vasodilation and sweating. These responses may continue indefinitely in response to sustained raised temperature of the hypothalamus. These physiological cooling responses will act to lower the body temperature of the patient.
In humans, the hypothalamus is located near to the sphenoid sinus, one of the sinuses accessible through the nose or mouth. Heat may be applied via the sinuses, or more particularly to the sphenoid sinus, in order to warm the hypothalamus and so to trigger a cooling response. Alternatively, heat may be applied directly to the hypothalamus. Heating of the hypothalamus may be accomplished with little heating of surrounding brain regions. Heat applied near the surface of the skull will penetrate a small distance, but blood flow and other thermal effects will cause the heating to be localized to the portion of the brain nearest the application of the heat. Thus, mild local heating of the sphenoid sinus or other nasal passages or sinuses in order to warm the bypothalamus would not cause undue heating of other portions of the brain. Alternatively, warming the nasal passages themselves can trigger sweating and so be effective for lowering body temperature.
Accordingly, a primary object of the present invention is to provide a method for inducing hypothermia which does not require cooling measures such as application of cold packs, cold blankets, infusion of cold saline, does not require drastic invasive measures or drugs, and would not oppose an animal""s physiological temperature control mechanisms, but would instead make use of them to achieve hypothermia.
It is a further object of the invention to provide a method of inducing hypothermia by applying heat to a nasal passage.
It is a further object of the invention to provide a method of inducing hypothermia by applying heat to a sinus of an animal. In particular, it is an object of the present invention to provide a method of inducing hypothermia in a person by applying heat to a sphenoid sinus.
It is a further object of the invention to provide a method of inducing hypothermia by warming the hypothalamus of an animal.
It is another object of the invention to provide an apparatus for warming a nasal passage of an animal.
It is another object of the invention to provide an apparatus for warming a sinus of an animal.
It is a further object of the invention to provide an apparatus for warming a sphenoid sinus.
It is another object of the invention to provide an apparatus for warming the hypothalamus of an animal.
It is another object of the invention to provide an apparatus for introducing compounds into a nasal passage of an animal.
It is a further object of the invention to introduce compounds into a sinus of an animal.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect, the invention is a method for inducing hypothermia which comprises providing a heat-generating means and, with this heat generating means, applying heat to a nasal passage, or a nasal passage and a sinus, or a nasal passage, sinus and hypothalamus, or to a sinus and hypothalamus, or to the hypothalamus. This application of heat to a nasal passage, or a nasal passage and sinus, or sinus and hypothalamus, or hypothalamus will result in a physiological response effective to lower the body temperature of the animal so treated.
In another aspect, this invention is an apparatus for applying heat to a nasal passage, or a nasal passage and a sinus, or a nasal passage, sinus and hypothalamus, or to a sinus and hypothalamus, or to the hypothalamus. Application of heat through the use of said apparatus to a nasal passage, or a nasal passage and a sinus, or a sinus and the hypothalamus, or the hypothalamus will result in a physiological response effective to lower the body temperature of the animal so treated.xe2x80x9d